Oncolytic adenoviruses for treatment of brain tumours

Standard therapies are not capable of curing patients with malignant glioma; more than 90% of patients die within 2 years after diagnosis. Gene therapy appeared as a promising new approach for this disease. However, results of clinical trials with replication deficient viral vectors were disappointing. The main reasons being poor transduction efficiency of adenovirus towards glioma cells and limited spread and distribution of the vector in the tumour. With the increasing knowledge of viral genetics and its functions, an attractive alternative tool to kill malignant glioma cells has been developed: Replicating adenovirus as an oncolytic agent. This type of therapy, also referred to as virotherapy, has the potential to overcome some of the limitations connected with replication deficient adenoviral vectors. In this review the authors describe the latest developments in strategies that are being used to create a tumour- or glioma- selective replicating adenovirus. Special attention is given to the methods of viral delivery to an infiltrating tumour in the brain, regarding optimal dose and toxicity. Furthermore, the role of conventional antitumour treatments, such as irradiation and chemotherapy, in enhancing the effect of virotherapy is being emphasised.     

Lack of definitive presurgical pathological diagnosis is associated with inadequate surgical margins in breast-conserving surgery

PurposeTo determine the impact of definitive presurgical diagnosis on surgical margins in breast-conserving surgery (BCS) for primary carcinomas; clinicopathological features were also analyzed.MethodsThis retrospective study included women who underwent BCS for primary carcinomas in 2016 and 2017. Definitive presurgical diagnosis was defined as having a presurgical core needle biopsy (CNB) and not being upstaged between biopsy and surgery. Biopsy data and imaging findings including breast density were retrieved. Inadequate surgical margins (IM) were defined per latest ASCO and ASTRO guidelines. Univariable and multivariable analyses were performed.Results360 women (median age, 66) met inclusion criteria with 1 having 2 cancers. 82.5% (298/361) were invasive cancers while 17.5% (63/361) were ductal carcinoma in situ (DCIS). Most biopsies were US-guided (284/346, 82.0%), followed by mammographic (60/346, 17.3%), and MRI-guided (2/346, 0.6%). US and mammographic CNB yielded median samples of 2 and 4, respectively, with a 14G needle. 15 patients (4.2%) lacked presurgical CNB. The IM rate was 30.0%. In multivariable analysis, large invasive cancers (>20 mm), dense breasts, and DCIS were associated with IM (p = 0.029, p = 0.010, and p = 0.013, respectively). Most importantly, lack of definitive presurgical diagnosis was a risk factor for IM (OR, 2.35; 95% CI: 1.23–4.51, p = 0.010). In contrast, neither patient age (<50) nor aggressive features (e.g., LVI) were associated with IM.ConclusionLack of a definitive presurgical diagnosis was associated with a two-fold increase of IM in BCS; other risk factors were dense breasts, large invasive cancers, and DCIS.     

Dual-energy computed tomography imaging to determine atherosclerotic plaque composition: A prospective study with tissue validation

BackgroundIdentifying vulnerable coronary plaque with coronary CT angiography is limited by overlap between attenuation of necrotic core and fibrous plaque. Using x-rays with differing energies alters attenuation values of these components, depending on their material composition.ObjectivesWe sought to determine whether dual-energy CT (DECT) improves plaque component discrimination compared with single-energy CT (SECT).MethodsTwenty patients underwent DECT and virtual histology intravascular ultrasound (VH-IVUS). Attenuation changes at 100 and 140 kV for each plaque component were defined, using 1088 plaque areas co-registered with VH-IVUS. Hounsfield unit thresholds that best detected necrotic core were derived for SECT (conventional attenuation values) and for DECT (using dual-energy indices, defined as difference in Hounsfield unit values at the 2 voltages/their sum). Sensitivity of SECT and DECT to detect plaque components was determined in 77 segments from 7 postmortem coronary arteries. Finally, we examined 60 plaques in vivo to determine feasibility and sensitivity of clinical DECT to detect VH-IVUS–defined necrotic core.ResultsIn contrast to conventional SECT, mean dual-energy indices of necrotic core and fibrous tissue were significantly different with minimal overlap of ranges (necrotic core, 0.007 [95% CI, –0.001 to 0.016]; fibrous tissue, 0.028 [95% CI, 0.016–0.050]; P < .0001). DECT increased diagnostic accuracy to detect necrotic core in postmortem arteries (sensitivity, 64%; specificity, 98%) compared with SECT (sensitivity, 50%; specificity, 94%). DECT sensitivity to detect necrotic core was lower when analyzed in vivo, although still better than SECT (45% vs 39%).ConclusionsDECT improves the differentiation of necrotic core and fibrous plaque in ex vivo postmortem arteries. However, much of this improvement is lost when translated to in vivo imaging because of a reduction in image quality.     

局麻单孔腹腔镜双极电凝与经腹近端抽芯包埋两种输卵管绝育术对生殖激素近期影响的对比观察

目的:比较观察局麻单孔腹腔镜双极电凝输卵管绝育术与经腹近端抽芯包埋输卵管绝育术对卵巢功能的影响。方法:在贵州省内14个县随机抽取2014年10月~2015年10月行上述两种输卵管绝育术妇女各100例,测定卵巢基础激素(FSH、LH和E2)。结果:共133例研究对象进入观察,其中腹腔镜输卵管绝育术组82名,年龄28.84±4.02岁;开腹输卵管绝育术组51名,年龄27.61±4.20岁。两组术后1个月的卵巢基础性激素平均水平无统计学改变;术后1个月基础FSH≥10U/L、基础FSH/LH升高2的比例开腹组明显高于腹腔镜组。结论:腹腔镜输卵管绝育术近期对卵巢功能的影响小于开腹输卵管绝育术。     

Longitudinal study of diffusion tensor imaging properties of affected cortical spinal tracts in acute and chronic hemorrhagic stroke

This study investigated the clinical value of diffusion tensor imaging (DTI) in predicting the motor outcome in patients with basal ganglia hemorrhage. This prospective study included 23 patients assessed with DTI to measure the fractional anisotropy (FA) value in affected cortical spinal tract (CST) at three time points: day 0, day 30 and day 90 after onset. The motor function score (MFS) was applied to evaluate motor function and patients were divided into good and poor outcome groups according to the MFS on day 90. The mean FA value on day 0 was significantly lower in the poor outcome group than in the good outcome group (p < 0.01). FA value gradually decreased in the poor outcome group until day 90 after onset, while it continuously increased in the good outcome group. The MFS obtained at day 90 after onset was significantly correlated with the initial FA value in the affected cerebral peduncle (r = −0.926, p < 0.01). Receiver operating characteristic curve analysis showed that the FA value on day 0 could predict motor function outcome with a sensitivity of 88.89% and specificity of 92.86% at the initial FA value of 0.45. The FA value of affected CST in acute cerebral hemorrhage may valuably predict the motor function outcome and its dynamic change may represent the Wallerian degeneration in motor tracts after hemorrhagic stroke.     

A rice chloroplast transit peptide sequence does not alter the cytoplasmic localization of sheep serotonin N‐acetyltransferase expressed in transgenic rice plants

Ectopic overexpression of melatonin biosynthetic genes of animal origin has been used to generate melatonin‐rich transgenic plants to examine the functional roles of melatonin in plants. However, the subcellular localization of these proteins expressed in the transgenic plants remains unknown. We studied the localization of sheep (Ovis aries) serotonin N‐acetyltransferase (OaSNAT) and a translational fusion of a rice SNAT transit peptide to OaSNAT (TS:OaSNAT) in plants. Laser confocal microscopy analysis revealed that both OaSNAT and TS:OaSNAT proteins were localized to the cytoplasm even with the addition of the transit sequence to OaSNAT. Transgenic rice plants overexpressing the TS:OaSNAT fusion transgene exhibited high SNAT enzyme activity relative to untransformed wild‐type plants, but lower activity than transgenic rice plants expressing the wild‐type OaSNAT gene. Melatonin levels in both types of transgenic rice plant corresponded well with SNAT enzyme activity levels. The TS:OaSNAT transgenic lines exhibited increased seminal root growth relative to wild‐type plants, but less than in the OaSNAT transgenic lines, confirming that melatonin promotes root growth. Seed‐specific OaSNAT expression under the control of a rice prolamin promoter did not confer high levels of melatonin production in transgenic rice seeds compared with seeds from transgenic plants expressing OaSNAT under the control of the constitutive maize ubiquitin promoter.     

Co-expression of cancer testis antigens and topoisomerase 2-alpha in triple negative breast carcinomas

Triple negative breast cancers (TNBC) are characterized by aggressive tumor biology, lack of targeted treatments and poor prognosis. Anthracyclins were shown to induce immunogenic death in target cells, potentially leading to “endogenous” vaccination. We comparatively assessed expression of cancer testis antigens (CTA) and topoisomerase 2-alpha (TOPO2A), a well defined molecular target of anthracyclins, in TNBC fully characterized for basal-like (BL) immunophenotype, BL morphology and conventional clinicopathological factors. The study included 83 patients undergoing surgery between January 2003 and December 2009. Tissue sections were stained with CK5/6, CK14, EGFR, Ki-67, TOPO2A, MAGE-A1, MAGE-A10, NY-ESO and multi-MAGE-A specific reagents. Of the 83 TNBC, >66.3% had BL immunophenotype and 48.2% had BL morphology. MAGE-A1 specific staining was most frequently detectable (69.2%), followed by multi-MAGE-A (58%), NY-ESO (27.1%) and MAGE-A10 (16%) specific staining. MAGE-A10 expression significantly correlated with tumor size (p = 0.026). Furthermore, MAGE-A1, MAGE-A10 and multi-MAGE-A specific stainings significantly correlated with advanced clinical stage (p = 0.024, p = 0.041, p = 0.031, respectively). We found no significant association between CTA expression and disease free (DFS) or overall survival (OS). Most interestingly, a significant correlation was observed between expression of MAGE-A10 and NY-ESO and expression of TOPO2A (p = 0.005, p = 0.013). Expression of defined CTA and TOPO2A are significantly correlated in TNBC. Considering the limited therapeutic options for TNBC, these findings might suggest novel forms of combination therapies that should be further explored.